The Rho family of Ras-like GTPases, which includes Rho, Rac and Cdc42, control actin-based cytoskeletal rearrangements (reviewed in Hall, Annu. Rev. Cell Biol. 10:31-54, 1994; Zigmond, Curr. Opin. Cell Biol. 8:66-73, 1996). Rho regulates receptor-mediated assembly of focal adhesions and stress fibers (Ridley and Hall, Cell 70:389-399, 1992), while Rac regulates the formation of membrane ruffles (Ridley et al., Cell 70:401-410, 1992) and Cdc42 controls the formation of filopodia (Nobes and Hall, Cell 81:53-62, 1995). Rho proteins have also been shown to be important in the regulation of cell proliferation (reviewed in Symons, Trends Biochem. Sci. 21:178-181, 1996). As members of the Ras superfamily, Rho proteins function as molecular switches, having an active, GTP-bound form, and an inactive, GDP-bound form. The active, GTP-bound form, is negatively regulated by GTPase activating proteins (GAPs) which enhance the intrinsic GTPase activity of Rho proteins. A number of GAPs that are active on proteins of the Rho family have been identified (reviewed in Lamarche and Hall, TIG 10:436-440, 1994). These include p50RhoGAP (Lancaster et al., J. Biol. Chem. 269:1137-1142, 1994), Myr5 (Reinhard et al., EMBO J. 14:697-704, 1995), and p190 (Settleman et al., Nature 359:153-154, 1992) which are also active on Rae and Cdc42. Another GAP, p122-RhoGAP (Homma and Emori, EMBO J. 14:286-291, 1995) appears to be specific for Rho.
Intracellular protein tyrosine phosphatases (PTPs) are a diverse group of proteins involved in signal transduction (reviewed in Streuli, Curr. Opin. Cell Biol. 8:182-188, 1996). They contain a conserved PTP domain which specifically dephosphorylates tyrosine residues and, in addition, domains that regulate their subcellular localization and activity (reviewed in Mauro and Dixon, Trends Biochem. Sci. 19:151-155, 1994). For example, the SH2 domains of SHP-1 and SHP-2 enables these PTPs to localize to and interact with activated growth factor receptors (Mauro and Dixon, 1994). Correct localization of PTPs is of importance, since the PTP domains usually have broad substrate specificity.
PTPL1 (Saras et al., J Biol. Chem. 269:24082-24089, 1994) also called PTP-BAS (Maekawa et al., FEBS Lett. 337:200-206, 1994), hPTP1E (Banville et al., J. Biol. Chem. 269:22320-22327, 1994) and FAP-1 (Sato et al., Science 268:411-415, 1995), is a 250 kDa protein expressed in many tissues and cell lines. PTPL1 is fully described in PCT published application WO95/06735. It contains an N-terminal leucine zipper motif followed by a domain with homology to the Band 4.1 superfamily. Band 4.1 -like domains are found in proteins involved in the linkage of actin filaments to the plasma membrane (Arpin et al., Curr. Opin. Cell Biol. 6:136-141, 1994). Five PDZ domains [PDZ is derived from PSD-95 (Cho et al., Neuron 9:929-942, 1992), Dlg-A (Woods and Bryant, Cell 66:451-464, 1991) and ZO-1 (Itoh et al., J. Cell. Biol. 121:491-502, 1993), each of which contains three such domains] are present between the Band 4. 1-like domain and the C-terminal PTP domain. These domain structures of about 90 amino acid residues have also been called GLGF repeats or DHRs and are identified in a variety of proteins (Ponting and Phillips, Trends Biochem. Sci. 20:102-103, 1995). A PDZ domain of PTPL1 has been shown to interact with the C-terminal tail of the membrane receptor Fas (Sato et al., 1995) and PDZ domains of PSD-95 bind to the C-terminals of the NMDA-receptor and Shaker-type K.sup.+ channels (Kim et al., Nature 378:85-88, 1995; Komau et al., Science 269:1737-1740, 1995). The crystal structures of two PDZ domains have recently been published (Doyle et al., Cell 85:1067-1076, 1996; Morais Cabral et al., Nature 382:649-652, 1996).
There exists a need to influence the receptor-mediated intracellular signal transduction pathways to treat disease. There also exists a need to identify the gene(s) responsible for increased or decreased signal transduction and to provide a genetic therapy for treating diseases resulting from aberrant signal transduction.
An object of the invention is to provide compounds that desirably influence the signal transduction by the Rho family of Ras-like GTPases.
Another object of the invention is to provide therapeutics for treating diseases resulting from aberrant signal transduction by the Rho family of Ras-like GTPases. Still another object of the invention is to provide diagnostics and research tools relating to PARG, PTPL1 and the Rho family of Ras-like GTPases. These and other objects will be described in greater detail below.